Synthesis of cyclopentanol

ABSTRACT

Process for synthesizing the lactone, (d1) 3,3a beta-4,5-6,6a- beta-hexahydro-4beta(3-hydroxyl-1-trans-octenyl)-5alpha-hydroxy-2-oxo-2H-cyclopenta[b]furan, a known intermediate for producing prostaglandin E 2  and F 2 α  and a process for preparing II-desoxy and II-alkyl prostaglandins from dihydroresorcyclic acid.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 613,137 filed Sept. 15, 1975,now U.S. Pat. No. 4,005,110, which in turn is a divisional applicationof Ser. No. 381,322 filed July 20, 1973, now abandoned, which in turn isa continuation-in-part of our pending U.S. application Ser. No. 300,633,filed Nov. 25, 1972 now abandoned.

BACKGROUND OF THE INVENTION

Prostaglandins are well known therapeutic agents. For example,prostaglandin F₂α and E₂ are known agents for inducing labor in pregnantwomen and for the therapeutic termination of pregnancy.

In an article by Corey et al. entitled "Stereo Controlled Synthesis ofProstaglandin F₂α and E₂ (dl)," Journal of American Chemical Society,Vol., 91, pp. 5675-5678 (1969), there is disclosed the synthesis ofvarious prostaglandins such as E₂ and F₂α from (dl) 3,3a beta-4,5,6,6abeta-hexahydro-4beta(3-hydroxy-1-trans-octenyl)-5alpha-hydroxy-2-oxo-2H-cyclopenta [b]furan, which has the formula: ##STR1##

SUMMARY OF THE INVENTION

In accordance with this invention, a process is provided forsynthesizing prostaglandins of the formula: ##STR2## wherein A is OH,OH, or OH; R is hydrogen, hydroxy and lower alkyl; R₁ is hydrogen; R₂ ishydroxy, or R₁ and R₂ taken together are oxo;

And the known intermediates of formula I from a compound of the formula:##STR3## wherein R₃ is hydrogen, lower alkyl or carboxy; and R₂ ' iscarboxymethyl or a potential carboxymethyl group;

Via an intermediate of the formula: ##STR4## wherein R₄ is carboxy, acarboxy protected with a group convertible thereto by hydrolysis,hydrogen or lower alkyl.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this application, the term "lower alkyl" includedboth straight chain and branched chain alkyl groups having from 1 to 7carbon atoms, such as methyl, ethyl and propyl, preferably methyl. Asused herein, the term "lower alkoxy" comprehends groups having from 1 to7 carbon atoms such as methoxy and ethoxy. As also used herein, the term"lower alkanoic acids" comprehends as alkanoic acid of 1 to 7 carbonatoms such as formic acid and acetic acid. As further used herein, theterm "halogen" or "halo", unless otherwise stated, comprehends fluorine,chlorine, bromine and iodine.

In the process of this invention, all compounds having one or moreasymmetric carbon atoms can be produced as racemic mixtures. Theseracemic mixtures which are obtained can be resolved at the appropriatesteps in the process of this invention by methods well known in the artdiscussed more fully below, whereupon subsequent products may beobtained as the corresponding optically pure enantiomers.

In the pictorial representation of the compounds given throughout thisapplication, a thickened tapered line ( ) indicates a substituent whichis in the β-orientation (above the plane of the molecule), a dotted line( ) indicates a substituent which is in the α-orientation (below theplane of the molecule) and a wavy line ( ) indicates a substituent whichis in either the α- or β-orientation. It is to be understood that thepictorial representations of the compounds given throughout thespecification are set forth for convenience and are to be construed asinclusive of other forms including enantiomers and racemates and are notto be construed as limited to the particular form shown.

As also used herein, the term "aryl" signifies mononuclear aromatichydrocarbon groups such as phenyl, tolyl, etc. which can beunsubstituted or substituted in one or more positions with a loweralkylenedioxy, a halogen, a nitro, a lower alkyl or a lower alkoxysubstituent, and polynuclear aryl groups such as naphthyl, anthryl,phenanthryl, azulyl, etc., which can be substituted with one or more ofthe aforementioned groups. The preferred aryl groups are the substitutedand unsubstituted mononuclear aryl groups, particularly phenyl. The term"aryl lower alkyl" comprehends groups wherein aryl and lower alkyl areas defined above, particularly benzyl. The term "aryl lower alkanoicacid" comprehends acids wherein "aryl" and "lower alkanoic acid" are asdefined above, particularly benzoic acid.

As still further used herein, the term "carboxy protected with a groupconvertible thereto by hydrolysis" comprehends any conventional organicacid protecting group which can be removed by hydrolysis. The preferredorganic acid protecting groups are the esters. Any conventional esterthat can be hydrolyzed to yield the acid can be utilized as theprotecting group. Exemplary esters useful for this purpose are the loweralkyl esters, particularly methyl and ethyl ester, the aryl esters,particularly phenyl ester and the aryl lower alkyl esters, particularlybenzyl ester.

As used herein, the term "hydrolyzable ester or ether group" designatesany ester or ether which can be hydrolyzed to yield the hydroxy group.Exemplary ester groups useful for this purpose are those in which theacyl moiety is derived from a lower alkanoic, an aryl lower alkanoic,phosphoric, carbonic or a lower alkane dicarboxylic acid. Among theacids which can be utilized to form such ester groups are the acidanhydrides and the acid halides, preferably chlorides or bromides, withthe lower alkanoic acid anhydrides, e.g., acetic anhydride and caproicanhydride, the aryl lower alkanoic acid anhydrides, e.g., benzoic acidanhydrides, lower alkane dicarboxylic acid anhydrides, e.g., succinicanhydride, and chloroformates, e.g., trichloroethylchloroformate, beingpreferred. A suitable ether protecting group is, for example, thetetrahydropyranyl ether or 4-methoxy-5,6-dihydro-2H-pyranyl ether.Others are arylmethyl ethers such as benzyl, benzhydryl, or tritylethers or α-lower alkoxy lower alkyl ether, for example, methoxymethylor allylic ethers, or alkyl silyl ethers such as trimethyl silyl ether.

As still further used throughout this application, the term "potentialcarboxymethyl group" comprehends a group which can be converted tocarboxymethyl. In accordance with this invention, any conventional groupconvertible to carboxymethyl can be utilized. Among the preferredpotential carboxymethyl groups are the groups which can be converted orhydrolyzed to a carboxymethyl group. Exemplary potential carboxymethylgroups are the groups: ##STR5## wherein R₁ ' is hydrogen or lower alkyland the dotted bond can be an additional unsaturated bond;

such as 2-propynyl and 2-butynyl and the groups:

    --CH.sub.2 --R'                                            (B)

wherein R' is a conventional group convertible to a carboxy group byhydrolysis;

such as methoxycarbonylmethyl and benzyloxycarbonylmethyl. Theparticularly preferred potential carboxymethyl group is 2-propenyl.

The compound of formula II includes prostaglandins E₂ and F₂α as well asother known prostaglandins, all of which are useful in the same manneras prostaglandin F₂α as an agent for inducing labor in pregnant womenand for the therapeutic termination of pregnancy.

The compound of formula III is formed from alpha-dihydroresorcyclic acidor a compound of the formula: ##STR6## wherein R₃ ' is hydrogen or loweralkyl; by treating dihydroresorcyclic acid or the compound of formula IVwith alpha-chloro acetic acid or a potential carboxymethyl halide of theformula:

    R.sub.2 'X.sub.1                                           XVIII

wherein R₂ ' is as above; X₁ is chlorine, bromine or iodine, preferablybromine.

Preferably a potential carboxymethyl halide is utilized, of the formula:##STR7## wherein X₁ and R₁ ' are as above; and the dotted bond can be anadditional unsaturated bond.

The reaction of dihydroresorcyclic acid or the compound of formula III-Awith the halide of formula XVIII can be carried out in an aqueous mediumcontaining an alkali metal hydroxide and in the presence of a powderedcopper catalyst. In carrying out this reaction, any conventional alkalimetal hydroxide can be utilized, with potassium hydroxide beingpreferred. In this reaction the alkali metal hydroxide can be present inan amount of from about 10 and 30% by weight of the aqueous medium. Incarrying out this reaction, temperature and pressure are not critical,and in general, the reaction can be carried out at room temperature (22°C.) and atmospheric pressure. Preferably, the reaction is carried out ata temperature of from about -10° C. to about 65° C., under an inert gasatmosphere. In carrying out this reaction, any conventional inert gassuch as nitrogen or argon may be utilized, and it is particularlypreferred to bubble the inert gas through the reaction mixture while, atthe same time, vigorously stirring the reaction mixture.

In accordance with the process of this invention, the compound offormula IV can be prepared from the compound of formula III via thefollowing reaction scheme: ##STR8## wherein R₃, R₄ and R₂ ' are asabove; R₆ is a potential carboxymethyl group; R₄ ' is hydrogen, loweralkyl or carboxy; R₅ is hydrogen, lower alkyl and a conventional groupconvertible to carboxy by hydrolysis; X is chlorine or bromine,preferably chlorine; R₃₀ is --CH₂ NO₂ or --C.tbd.N.

In accordance with the process of this invention, the carboxysubstituent or substituents on the compound of formula III can beprotected by esterification. In obtaining the compound of formula VI,where R₅ and R₆ is a protected carboxy group, the compound of formulaIII can be esterified by any conventional means. In carrying out theprotection of the carboxy group, it is preferred to react the compoundof formula III with a lower alkanol or benzyl alcohol. This reaction canbe carried out by conventional esterification methods utilizingconventional inert organic solvents such as a lower alkanol, a loweralkyl ether, acetone, tetrahydrofuran, dioxane, diglyme, or an aliphaticor aromatic hydrocarbon. In general, the reaction is preferably carriedout in an excess of the alcohol reagent. This reaction is preferablycarried out in the presence of a catalytic amount of a mineral acid. Anyconventional mineral acid may be utilized, with sulfuric acid beingpreferred. In carrying out this reaction, temperature and pressure arenot critical, and in general, the reaction can be carried out at roomtemperature and atmospheric pressure. However, it is generally preferredto utilize temperatures of about 50° C. to about 150° C., with thereflux temperature of the reaction mixture being preferred.

It should be particularly noted that where R₂ ' in the compound offormula III is carboxymethyl, esterification of the compound of formulaIII, where R₃ is carboxy, also esterifies the carboxymethyl substituentas well as the carboxy substituent defined by R₃. Hence, esterificationof the compound of formula III converts each carboxy substituent thereonto a carboxy protecting group removable by hydrolysis.

The compound of formula VII can be obtained by chlorinating orbrominating the compound of formula VI. In carrying out this reaction,any conventional chlorinating or brominating agent can be utilized.Among the preferred chlorinating agents are chlorine dissolved in achlorinated hydrocarbon, tert-butylhypochlorite, andN-chlorosuccinimide, particularly tert-butylhypochlorite. Among thepreferred brominating agents are included bromine dissolved in ahalogenated hydrocarbon or n-bromo-succinimide or acetamide. Thisreaction can be carried out in an inert organic solvent. In carrying outthis reaction, any conventional, inert organic solvent can be utilized,such as the halogenated hydrocarbons, the lower alkanols, diethyl etherand tetrahydrofuran. In utilizing tert-butylhypochlorite, the loweralkanols, particularly methanol, are the preferred solvents. In carryingout this reaction, temperature and pressure are not critical, and ingeneral, the reaction can be carried out at room temperature andatmospheric pressure. In carrying out this reaction, temperatures ofabout -10° C. to about 100° C. are generally utilized with temperaturesof from 0° C. to 20° C. being particularly preferred.

The cyclopentenyl compound of formula VIII can be obtained by the ringcontraction of the compound of formula VII. In carrying out this ringcontraction, the compound of formula VII is preferably heated to anelevated temperature in the presence of a non-hydroxyl base. In carryingout this reaction, any conventional non-hydroxyl base can be utilized.In general, the anhydrous alkali metal carbonates, sodium bis-trimethylsilylamide, lithium diisopropylamide and powdered glass are thepreferred non-hydroxyl bases, particularly anhydrous sodium carbonate.This reaction can be carried out in an inert organic, high-boilingsolvent, preferably under an inert gas atmosphere such as nitrogen orargon. In carrying out this reaction, any conventional inert organichigh-boiling solvent can be utilized with the aromatic hydrocarbons,being preferred, particularly xylene and mesitylene. In carrying outthis reaction, an elevated temperature of about 100° C. to about 200° C.can be utilized. In general, it is preferred to carry out this reactionat the reflux temperature of the reaction mixture, with a temperature ofabout 140° C. to about 170° C. being particularly preferred.

The compound of formula IX where R₃₀ is --CH₂ NO₂ can be obtained bytreating the compound of formula VIII with nitromethane in the presenceof a base. In carrying out this reaction, any conventional base may beutilized. Among the preferred bases are the lower alkoxides,particularly the alkali metal lower alkoxides, and the amines,particularly the tertiary and quaternary amines, and pyridine.Particularly preferred as the base is benzyltrimethylammonium hydroxide.This reaction can be carried out in an inert organic solvent. In thisreaction, any conventional, inert organic solvent can be utilized, suchas a lower alkanol, a lower alkyl ether, tetrahydrofuran, dioxane ordiglyme. In carrying out this reaction, it is preferred to utilize anexcess of nitromethane as the solvent. In carrying out this reaction,temperature and pressure are not critical, and in general, the reactioncan be carried out at room temperature and atmospheric pressure. Incarrying out this reaction, it is preferred to utilize a temperature ofabout -30° C. to the reflux temperature of the reaction mixture with atemperature of about 100° C. being particularly preferred.

The compound of formula IX where R₃₀ is --C.tbd.N can be prepared byreacting the compound of formula IX with a cyanolating agent. Anyconventional cyanolating agent can be utilized. Among the preferredcyanolating agents are dilower alkyl aluminum cyanide, and thecyanohydrin of acetone. Where a cyanohydrin of acetone is utilized, thereaction is carried out in the presence of an alkali metal carbonate inan aqueous alcoholic medium such as aqueous ethanol. Where a dialkylaluminum cyanide is utilized, the reaction is carried out in an inertorganic solvent such as toluene or benzene. In carrying out thisreaction, temperature and pressure are not critical and this reactioncan be carried out at room temperature or atmospheric pressure. Ifdesired, higher or lower temperatures can be utilized. Generally,temperatures of from 0° to 50° C. are preferred.

In the formation of the compound of formula IX from the compound offormula VIII, the substituents R₅ and R₆ have the same planarorientation about the cyclopentyl radical, i.e., either both above orboth below the plane of the cyclopentyl radical. On the other hand, thenitromethane substituent is attached to the molecule on the oppositeside of the plane as the substituents R₅ and R₆. This orientation iscarried out throughout the rest of the process whereby a compound offormula IX is converted to a compound of formulae I or II.

The compound of formula X is obtained from the compound of formula IX byconverting the potential carboxymethyl group to a carboxymethyl group.This conversion can be carried out in a conventional manner, such as bythe oxidative degradation of the compound of formula IX wherein R₆ is##STR9## and R₁ ' is as above, or by the hydrolysis of the compound offormula IX wherein R₆ is --CH₂ --R' and R' is as above.

In carrying out the oxidative degradation of the compound of formula IX,any conventional oxidizing agent which will selectively oxidize a2-propynyl or 2-propenyl group to form a carboxymethyl group can beutilized. In general, the alkali metal permanganates, osmiumtertoxide/periodate, and ozone are the preferred oxidizing agents, withpotassium permanganate being particularly preferred. This oxidativedegradation can be carried out in an inert solvent. In carrying out thisreaction, any conventional inert solvent can be utilized, such as waterand the organic solvents mentioned hereinbefore, with acetone beingpreferred. In carrying out this reaction, temperature and pressure arenot critical, and in general, a temperature of about -70° C. to thereflux temperature of the reaction mixture can be utilized with about-40° C. to about +20° C. being particularly preferred and about 0° C.being quite particularly preferred.

In carrying out the hydrolysis of the compound of formula IX, anyconventional method of hydrolysis can be utilized. Generally, it ispreferred to utilize a dilute aqueous mineral acid, such as sulfuricacid or an aqueous alkali such as sodium hydroxide.

It should be noted that as a result of the hydrolysis of the compound offormula IX, each substituent which is a conventional group convertibleto a carboxy group by hydrolysis, is converted to a free carboxysubstituent. For this reason, it is preferred that the potentialcarboxymethyl substituent be a group of formula XVIII-A.

If desired, the acid of formula X is converted to its optically activeisomeric form by any conventional means of resolving an acid. Incarrying out the optical resolution, any conventional basic opticallyactive resolving agent can be reacted with the acid of formula X toresolve the optical enantiomers. The preferred basic resolving agentsare the amines, particularly α-phenethylamine. In carrying out thisreaction, either enantiomer of the basic, optically active compound canbe utilized to separate the d,l-carboxy compound of formula X. Thisresolution can be carried out in an inert organic solvent. In thisreaction, any conventional inert organic solvent can be utilized, suchas the solvents mentioned hereinbefore, preferably tetrahydrofuran. Inthis reaction, temperature and pressure are not critical, and thereaction can be carried out at room temperature and atmosphericpressure. If desired, either optically active enantiomers of formula Xcan be converted by the process of this invention to a desired opticallyactive form of the compound of formula X. On the other hand, a racemateof the compound of formula X can be converted by the process of thisinvention to the racemate of formula I.

The compound of formula XI can be obtained by the selective reduction ofthe compound of formula X. In carrying out this reaction, the compoundof formula X can be treated with a reducing agent. In general, it ispreferred to convert the compound of formula X to the correspondingalkali metal carboxylate before reduction thereof.

The conversion of the compound of formula X to its alkali metalcarboxylate can be suitably carried out by treating the compound offormula X with an alkali metal lower alkoxide, with sodium methoxidebeing preferred. In carrying out this reaction, conventional methods ofconverting a carboxylic acid or dicarboxylic acid to an alkali metalsalt thereof can be utilized.

In carrying out the selective reduction of the compound of formula X togive the compound of formula XI, any conventional reducing agent whichwill selectively reduce to 4-keto group to a 4-hydroxy group withoutaffecting a carboxyl group can be utilized. In general, a hydridereducing agent is preferred, such as an alkali metal hydride orborohydride. A particularly preferred reducing agent is lithiumperhydro-9b-boraphenalylhydride. In carrying out this reaction,temperature and pressure are not critical, and the reaction can becarried out at room temperature and atmospheric pressure. In general,the reaction is preferably carried out at a temperature of from about-100° C. to the reflux temperature of the reaction mixture, with lessthan about 0° C. being the particularly preferred temperature and about-78° C. being quite particularly preferred. This reaction can be carriedout in the presence of an inert organic solvent. In carrying out thisreaction, any conventional inert organic solvent, such as the solventsmentioned hereinbefore, can be utilized.

The compound of formula XI can be converted to the compound of formulaXII by heating the compound of formula XI in an inert organic solvent.In carrying out this conversion, temperature and pressure are notcritical and, in general, the reaction can be carried out at atemperature of from about 50° C. to about 100° C. and at atmosphericpressure, with the reflux temperature being preferred. This reaction canbe carried out in a conventional inert organic solvent such as thesolvents mentioned hereinbefore, preferably tetrahydrofuran.

In carrying out the lactonizing procedure, only the isomer of formula XIwhere the hydroxy group is on the same side of the plane of the moleculeas the carboxymethyl substituent, lactonizes to form the compound offormula XII. Hence, in the conversion of the compound of formula XI tothe compound of formula XII, the compound of formula XI-A is produced asa side product. The compound of formula XI-A can be separated from thecompound of formula XII by forming the water soluble acid salt of thecompound of formula XI-A. A conventional base such as an alkali metalcarbonate or bicarbonate can be utilized to form the water solublealkali metal salt of the compound of formula XI-A. After separation ofthe compound of formula XI-A from the compound of formula XII via itswater soluble acid salt thereof, the compound of formula XI-A can beconverted back to the compound of formula X by oxidation utilizing anoxidizing agent such as the Jones Reagent or chromium trioxide orpotassium permanganate. Any of the conditions conventional in oxidizingwith these oxidizing agents can be utilized in oxidizing the compound offormula XI-A to the compound of formula X.

The compound of formula XII where R₃₀ is --CH₂ NO₂ can be directlyconverted to the compound of formula XVI by oxidizing the compound offormula XII with an oxidizing agent which selectively oxidizes anitromethyl group to an aldehyde. The preferred oxidizing agents are thealkali metal permanganates, sodium permanganate being particularlypreferred. In carrying out this reaction, the compound of formula XII isconverted to its aci-nitro salt before treatment with the permanganate.

The compound of formula XII where R₃₀ is --CH₂ NO₂ can be converted toits aci-nitro salt by treatment with an alkali metal lower alkoxide,preferably lithium methoxide. In carrying out this reaction, temperatureand pressure are not critical, and in general, the reaction can becarried out at room temperature and atmospheric pressure. This reactioncan be carried out in an inert organic solvent. In this reaction, anyconventional inert organic solvent may be utilized, such as the solventsmentioned hereinbefore with methanol being preferred.

The oxidation of the aci-nitro salt of the compound of formula XII canbe carried out in the presence of an inert organic solvent or water. Inthis reaction, any conventional inert organic solvent may be utilizedsuch as tetrahydrofuran, dioxane, acetone, diglyme or a lower alkylether. In carrying out this reaction, temperature and pressure are notcritical and the reaction can be carried out at room temperature andatmospheric pressure. In general, it is preferred to carry out thisreaction at a temperature of about -10° C. to about +75° C. with atemperature of about 0° C. being particularly preferred.

Alternatively, the compound of formula XII can be converted to thecompound of formula XVI via intermediates XIII, XIV, XV and XVII. Inthis procedure, the compound of formula XII is first hydrogenated toform the compound of formula XIII. This hydrogenation is carried out inthe presence of a hydrogenation catalyst.

Before hydrogenation and before conversion to its acinitro salt, thecompound of formula XII, wherein R₄ is carboxy, is preferably firstprotected by a conventional protecting group convertible to a carboxygroup by hydrolysis. The conversion of R₄ from carboxy to a groupconvertible to carboxy can be carried out in a conventional manner byesterification, preferably in accordance with the esterification of thecompound of formula III above. In the hydrogenation of the compound offormula XII, any conventional hydrogenation catalyst can be utilizedsuch as Raney-nickel, a noble metal, and aluminum amalgam. In thisreaction, the use of a noble metal such as platinum or palladium ispreferred. In carrying out this reaction, temperature and pressure arenot critical, and in general, the reaction can be carried out at roomtemperature and at atmosphereic pressure. Preferably, the reaction iscarried out at from about 1 to about 5 atmospheres of pressure and about0° C. to about 20° C. The hydrogenation reaction can be carried out inan inert organic solvent. In carrying out this reaction, ay conventionalinert organic solvent may be utilized such as the solvents hereinbeforementioned, preferably a lower alkanol, particularly ethanol.

The compound of formula XIV can be obtained by treating the compound offormula XIII with a chlorinating or brominating agent, preferably achlorinating agent. In carrying out this halogenation, any conventionalchlorinating or brominating agent may be utilized, with tertiarybutylhypochlorite being the preferred chlorinating agent. This reactioncan be carried out in an inert organic solvent. In this reaction, anyconventional inert organic solvent may be utilized, such as the solventsmentioned hereinbefore. In carrying out this reaction, temperature andpressure are not critical and the reaction can be carried out at roomtemperature and atmospheric pressure. If desired, higher or lowertemperatures may be utilized. Generally, this reaction is carried out attemperatures of -100° C. to 50° C. with about 0° C. to 10° C. beingpreferred.

The compound of formula XV can be obtained by reacting the compound offormula XIV with a lower alkoxide preferably an alkali metal loweralkoxide such as sodium methoxide. This reaction is preferably carriedout in an inert organic solvent. In carrying out this reaction, anyconventional inert organic solvent may be utilized, such as the solventshereinbefore mentioned. Among the preferred solvents are the loweralkanols. In carrying out this reaction, temperature and pressure arenot critical, and the reaction can be carried out at room temperatureand atmospheric pressure. In this reaction, temperatures of about 0° C.to about 100° C. are generally utilized with the reflux temperaturebeing preferred.

The compound of formula XVI can be obtained by the hydrolysis of thecompound of formula XV. In carrying out this reaction, the compound offormula XV is preferably treated with a dilute acid whereby the iminomoiety in the compound of formula XV is hydrolyzed to the aldehydemoiety without affecting any hydrolyzable carboxy protecting groupdefined by R₄. In carrying out this hydrolysis with a dilute acid, about0.05 N to about 2.0 N-aqueous acid solution is preferably utilized. Incarrying out this reaction, any conventional acid can be utilized, withthe mineral acids being particularly preferred and sulfuric acid beingquite particularly preferred. This reaction can be carried out in wateror in an inert organic solvent. Any conventional inert organic solventmay be utilized in this hydrolysis reaction, with the lower alkanolsbeing preferred. In carrying out this reaction, temperature and pressureare not critical, and the reaction can be carried out at roomtemperature and atmospheric pressure. Generally, this reaction iscarried out at a temperature of about 0° C. to about 50° C., with 20° C.being preferred.

The compound of formula XVI can further be alternatively obtained byoxidizing the compound of formula XIII to an oxime of formula XVII, andhydrolyzing the oxime to the aldehyde of formula XVI.

In carrying out the oxidation of the compound of formula XIII anyconventional oxidizing agent for converting an amine to an oxime may beutilized, such as hydrogen peroxide, an alkali metal tungstate or analkali metal molybdate. In carrying out this reaction, temperature andpressure are not critical and the reaction can be carried out at roomtemperature and atmospheric pressure. In general, the reaction ispreferably carried out at a temperature of about 0° C. to about 50° C.This reaction can be carried out in an inert organic solvent. Incarrying out this reaction, any conventional inert organic solvent suchas the solvents mentioned hereinbefore can be utilized, withtetrahydrofuran being preferred.

The hydrolysis of the oxime of formula XVII to the compound of formulaXV can be carried out in the presence of a bisulfite, preferably analkali metal bisulfite. By this hydrolysis step with a bisulfite, theoxime moiety is hydrolyzed to the aldehyde moiety without hydrolyzingthe carboxy protecting group defined by R₄. In this reaction,temperature and pressure are not critical and the reaction can becarried out at room temperature and atmospheric pressure. In general,the reaction is preferably carried out at a temperature of about 0° C.to about 100° C. This reaction can be carried out in an inert organicsolvent. In this reaction, any conventional inert organic solvent, suchas the solvents mentioned hereinbefore, can be utilized with the loweralkanols being preferred.

The compound of formula IV can be obtained by treating the compound offormula XVI with either a phosphorane of the formula: ##STR10## whereinR₆ ', R₆ " and R₆ "' are aryl or di(lower alkyl)amino;

or a phosphonate of the formula: ##STR11## wherein R₇ and R₇ ' are aryl,aryloxy or lower alkoxy. The double bond formed in the compound offormula IV by this reaction is a trans double bond.

The reaction of a phosphorane of formula XIX with the compound offormula XVI can, if desired, be carried out utilizing conventionalWittig conditions. Any of the conditions conventional in carrying outWittig reactions can be utilized in carrying out this reaction.

The reaction between the phosphonate of formula XX and the compound offormula XVI can be carried out by utilizing conditions conventional inHorner type reactions. Any of the conditions conventional in carryingout Horner type reactions can be utilized in carrying out this reaction.

Where R₄ is the compound of formula IV is a protected carboxy group,this compound can, if desired, be hydrolyzed by conventional means toform the corresponding compound of formula IV where R₄ is a free carboxygroup.

In accordance with this invention, the compound of formula IV is nextconverted to a compound of the formula: ##STR12## wherein R₄ is asabove.

The compound of formula XXI can be obtained by treating the compound offormula IV with a reducing agent. In carrying out this reaction, anyconventional reducing agent which will selectively reduce a keto-groupto a hydroxy group can be utilized. Preferred reducing agents are thehydrides, particularly the aluminum hydrides, such as the alkali metalaluminum hydrides, and the borohydrides, such as the alkali metalborohydrides, with zinc borohydride being quite particularly preferred.In carrying out this reaction, temperature and pressure are notcritical, and the reaction can be carried out at room temperature andatmospheric pressure or at elevated or reduced temperatures andpressures. Generally, it is preferred to carry out this reaction at atemperature of from -10° C. to the reflux temperature of the reactionmixture. This reduction reaction can be carried out in the presence ofan inert organic solvent. Any conventional inert organic solvent orwater can be utilized in carrying out this reaction, such as theconventional, inert organic solvents hereinbefore mentioned. Among thepreferred solvents are dimethoxy ethylene glycol and the ethers, such astetrahydrofuran, diethyl ether and dioxane.

The compound of formula XXI may be separated into its two isomers byconventional means to produce one isomer of the formula: ##STR13## andthe other isomer of the formula: ##STR14## wherein R₄ is as above. Anyconventional means of separation such as column chromatography, vaporphase chromatography, etc., can be utilized to carry out thisseparation.

The compound of formulae XXI, XXI-A or XXI-B can, if desired, beconverted to a compound of the formula: ##STR15## wherein R₄ is asabove; and R₁₂ is hydroxy or hydroxy protected with a hydrolyzable etheror ester protecting group;

by esterifying or etherifying the free hydroxy group with a hydrolyzableether or ester protecting group. This esterification or etherificationcan be carried out by conventional esterification or etherificationprocedures. Among the preferred hydrolyzable ester groups are loweralkanoyloxy with acetoxy being especially preferred. Among the preferredhydrolyzable ether groups are included tetrahydropyranyl.

In accordance with the process of this invention where R₄ is carboxy ora protected carbonyl group, either an isomer of the compound of formulaXXI-C or mixtures of these isomers can be converted to the compound offormula I (Coreys Intermediate).

Where R₄ in the compound of formula XXI-C is a protected carboxy groupand R₁₂ in the compound of XXI-C is a protected hydroxy group, theprotected carboxy group R₄ can be hydrolyzed while leaving the hydroxygroup R₁₂ protected by either an ester or ether group to produce acompound of the formula: ##STR16## wherein R₁₂ " is hydroxy protectedwith a hydrolyzable ether or ester group; and R₁₀ is --CH₂ --CH₂ --CH₂--CH₂ --CH₃ ;

via the following intermediates: ##STR17## wherein R₁₀ is as above; andR₁₂ ' is hydroxy or hydroxy etherified with a hydrolyzable etherprotecting group; and ##STR18## wherein R₁₀, R₄ ' and R₁₂ ' are asabove.

The compound of formula XXI-C where R₄ is a carboxy protecting group, isconverted to the compound of formula XXI-D by hydrolysis. Anyconventional method of basic hydrolysis can be utilized in thisprocedure. Among the preferred methods of converting the compound offormula XXI-C to the compound of formula XXI-D is by treating thecompound of formula XXI-C with a dilute aqueous alkali metal hydroxidesuch as dilute aqueous sodium hydroxide. This basic hydrolysis will alsohydrolyze R₁₂ where R₁₂ is an ester protecting group.

The compound of formula XXI-D is converted to the compound of formulaXXI-E by treating the compound of formula XXI-D with a dilute aqueousmineral acid at temperatures of from 0 to 25° C. Any conventionalaqueous acid can be utilized. Among the preferred acids are includeddilute aqueous 0.1N to 2N-hydrohalic acids such as 0.1N-hydrochloric and0.1N to 2N-aqueous sulfuric acid. The dilute mineral acid will nothydrolyze R₁₂ ' where R₁₂ ' is an ether protecting group.

The compound of formula XXIII where R₁₂ " is a hydrolyzable ester groupis prepared from the compound of formula XXI-E where R₁₂ ' is hydroxy bytreatment with an acid esterifying agent such as a lower alkanoic acidanhydride. Any conventional method for esterifying an alcohol can beutilized in this convention.

The compound of formula XXIII can be converted to the compound offormula I via the following intermediates: ##STR19## where R₁₂ " and R₁₀are as above and R₈ is an activated leaving group; ##STR20## wherein R₁₀and R₁₂ " are as above; and R₁₅ is the source of variation whichdistinguishes one per-organic acid from another. ##STR21## wherein R₁₀,R₁₅ and R₁₂ " are as above; and ##STR22## wherein R₁₀ R₁₅ and R₁₂ " areas above.

The compound of formula XXIII is converted to the compound of formulaXXIV by treating with an agent to provide an activated leaving group onthe carbonyl moiety. Any conventional activated leaving group which canbe displaced from the carbonyl moiety by a peracid to promote thecoupling of the peracid with the carbonyl moiety can be utilized as thesubstituent R₈. Among the preferred activated leaving groups are thechloride and bromide groups, particularly the chloride group. Anyconventional method of converting a hydroxy moiety on a free carboxyacid group to an activating leaving group can be utilized. Among thecompounds which react with the compound of formula XXIII to form anactivating leaving group are included oxalyl chloride and thionylchloride.

The compound of formula XXV can be obtained by treating the compound offormula XXIV with a peracid, preferably mchloroperbenzoic acid. In thisreaction, the activating leaving group R₈ is displaced from the carbonylmoiety by the peracid to form a mixed peranhydride of formula XXV. Thisreaction is preferably carried out in the presence of an organic base,such as triethylamine, collidene or pyridine, with pyridine beingparticularly preferred. This reaction can be carried out in an inertorganic solvent. In this reaction, any conventional inert organicsolvent can be utilized, such as the solvents mentioned hereinbefore.Alternatively, the reaction can be carried out in an organic base as setforth above. Preferably, the reaction is carried out in anhydrousdiethyl ether. In carrying out this reaction, temperature and pressureare not critical, and the reaction can be carried out at roomtemperature and atmospheric pressure. In general, it is preferred tocarry out the reaction at from about -20° C. to about +60° C. Incarrying out this reaction, any conventional perorganic acid can beutilized such as p-nitroperbenzoic acid. The preferred peroraganic acidsare the aromatic perorganic acids where the aromatic group issubstituted.

The compound of formula XXV can be directly produced from the compoundof formula XXIII by treating the compound of formula XXIII with aperorganic acid in the presence of dicyclohexylcarbodiimide. Thisreaction can be carried out in an inert organic solvent such as thesolvents mentioned hereinbefore. Among the preferred solvents are theether solvents such as tetrahydrofuran, diethyl ether, etc., and thehalogenated hydrocarbon solvents such as methylene chloride, etc. Incarrying out this reaction, temperatures of from -20° C. to +60° C. canbe utilized.

Upon refluxing the compound of formula XXV in an inert organic solvent,a mixture containing the compound of formula XXVII and XXVII-A isformed. This formation of this mixture is carried out by refluxing thecompound of formula XXV in an inert organic solvent. Any conventionalinert organic solvent can be utilized. Among the preferred inert organicsolvents are included aromatic hydrocarbon solvents such as benzene andtoluene.

The compound of formula I (Corey's Intermediate) can be obtained fromthe mixture of the compounds of formula XXVII and formula XXVII-A whereR₁₂ " is a hydrolyzable ester group by basic hydrolysis. In carrying outthis hydrolysis, the mixture is preferably treated with a dilue, aqueousalkali metal lower alkoxide. In this hydrolysis, any conventional alkalimetal lower alkoxides can be utilized. This reaction can be carried outin the presence of an inert organic solvent. In carrying out thisreaction, any conventional inert organic solvent can be utilized such asthe solvents mentioned hereinbefore, preferably the ether andhydrocarbon solvent, particularly tetrahydrofuran. In carrying out thisreaction, temperature and pressure are not critical, and the reactioncan be carried out at room temperature and atmospheric pressure.

Basic hydrolysis of the mixture containing the compound of formula XXVIIand the compound of the formula XXVII-A gives the compound of formula I.In the case where R₁₂ " is a hydrolyzable ester group, basic hydrolysisof the mixture directly produces Corey's Intermediate. On the otherhand, where R₁₂ " is a hydrolyzable ether protecting group, basichydrolysis produces the compound of formula I where the hydroxy group isprotected by a hydrolyzable ether protecting group. In this case, thiscompound is subjected to acid hydrolysis to produce Corey'sIntermediate. Any conventional method of hydrolyzing ether protectinggroups can be utlized in carrying out this procedure. Dilute aqueousorganic acids such as acetic acid or propionic acid can be utilized tocarry out this hydrolysis.

The compound of formula I is converted to known prostaglandins by theprocess disclosed in the article by Corey et al. Journal of AmericanChemical Society, Vol., 91, pp. 5675-5678 (1969).

In the compounds of formulae I, XXI-C, XXI-D, XXI-E, XXIII, XXIV, XXV,XXVII and XXVII-A, the hydroxy, R₁₂, R₁₂ ' and R₁₂ " substituents can bein either the alpha or beta orientation or these substituents maycontain a mixture of these groups in the alpha and beta orientation.

Compounds of the formula XXI-C where R₄ is hydrogen or alkyl, i.e.,compounds of the formula: ##STR23## wherein R₁₂ is as above; and R₁₁ ishydrogen or lower alkyl; can be converted to known prostaglandins of theformula: ##STR24## wherein R₁₁ is as above; via the followingintermediates: ##STR25## wherein R₁₀, R₁₁ and R₁₂ " are as above; and##STR26## wherein R₁₀, R₁₁ and R₁₂ " are as above.

The free hydroxy group in the compound of formula XXX where R₁₂ ishydroxy can be etherified or esterified by conventional means to formthe corresponding compound where R₁₂ is hydroxy protected with ahydrolyzable ether or ester group. This compound is converted to thecompound of formula XXXI by reduction with an alkyl aluminum hydridereducing agent. Any of the conditions conventional in utilizing thesereducing agents can be utilized to affect this conversion.

The compound of formula XXXI is converted to the compound of formulaXXXII by reaction with a phosphorane of the formula: ##STR27## whereinR₆ '", R₆ ' and R₆ " are as above; via a Wittig reaction. Any of theconditions standard in Wittig type reactions can be utilized in carryingout this reaction. In this Wittig reaction, the double bond formedthereby in the compound of formula XXXII is a "cis" double bond.

The compound of formula XXXII can be converted to the compound offormula II-A by conventional hydrolysis techniques utilized forhydrolyzing esters or ethers.

On the other hand, the compound of formula XXXII can be converted to aprostaglandin of formula: ##STR28## wherein R₁₀ and R₁₁ are as above;via an intermediate of the formula: ##STR29## wherein R₁₀, R₁₁ and R₁₂ "are as above.

The compound of formula XXXII is converted to the compound of formulaXXXIII by oxidation. Any conventional oxidizing agent which will converta hydroxy group to a keto group can be utilized in this conversion.Among the preferred oxidizing agents are chromate oxidizing agents suchas chromium trioxide. Any of the conditions conventionalin utilizingthese oxidizing agents can be utilized in carrying out these reactions.The compound of formula XXXIII is converted to the compound of formulaI-B by conventional hydrolysis procedures such as describedhereinbefore.

In the compounds of the formulae II-A, I-B, XXX, XXXI, XXXII and XXXIII,the hydroxy substituent attached to the straight chain on R₁₂ " and R₁₂can be in the alpha or beta configuration or can be mixtures ofsubstituents in the alpha or beta configuration.

The racemic products and intermediates of this invention can be resolvedinto their optically active components by a number of methods ofresolution well known in the art. The compounds which are acids aretreated with an optically active base in the manner describedhereinbefore to produce diastereoisomeric salts which can be separatedby crystallization. In addition, compounds containing a free hydroxygroup can be acylated with the acid chloride or anhydride of anoptically active acid in the presence of an esterification catalyst,e.g., d-camphorsulfonic acid, α-bromocamphorsulfonic acid and d- and1-6,6'-dinitrodiplenic acid to give diastereoisomeric esters which areresolvable by crystallization.

The examples which follow illustrate the invention. All temperatures arein degrees centrigrade (° C.). Dilute sulfuric acid is an aqueoussolution of 5% by weight sulfuric acid. Concentrated sulfuric acid is anaqueous solution of 98% by weight sulfuric acid. Dowex 50W-X8 (H+) is apolystyrene sulfonic acid -- cationic ion exchange resin. A - 540 (OH³¹)which is a polystyrene gel of trimethyl ammonium chloride is an anionicion exchange resin.

EXAMPLE 1 4-(2-Propenyl)-3,5-cyclohexanedione carboxylate

To a solution of 93.6 g. of alpha-dihydroresorcyclic acid in 264 ml of20 percent by weight aqueous potassium hydroxide was added 1.8 g ofcopper powder and 78 g of allyl bromide. Nitrogen was bubbled throughthe mixture which was stirred vigorously at room temperature for 5 1/2hours. 600 ml of 6 percent by weight aqueous sodium hydroxide was addedand the unreacted allyl bromide removed by two extractions with 100 mlportions of diethyl ether. The basic aqueous solution was cautiouslyacidified with ice-cooling with 20 percent by weight aqueous sulfuricacid to pH 2. The mixture was then extracted six times with 300mlportions of diethyl ether and dried with anhydrous magnesium sulfate.The combined, dried ether extracts were evaporated leaving a partiallysolid residue. Crystallization from ethyl acetate-petroleum ether gave afirst crop 25.8 g, m.p. 163°-165° C. and a second crop 30.0 g. m.p.148°-152° C., of 4-(2-propenyl)-3,5-cyclohexanedione carboxylate.

EXAMPLE 2 Methyl 4-(2-propenyl)-3,5-cyclohexanedione carboxylate

55.8 g of the 4-(2-propenyl)-cyclohexanedione carboxylate was dissolvedin 700 ml of methanol, 2 g of concentrated sulfuric acid was added, andthe mixture heated under reflux for 4 hours. Upon evaporation, theresidue was dissolved in 200 ml of tetrahydrofuran and 100 ml of waterand stirred at room temperature for 1 hour. Concentration of the mixtureto half its volume, addition of 200 ml of water, five extractions with250 ml portions of methylene chloride, gave upon evaporation of thedried (with magnesium sulfate) organic extracts crude product whichafter crystallization from ethyl acetate-petroleum ether afforded 38.75g of methyl 4-(2-propenyl)-3,5-cyclohexanedione carboxylate, m.p.130°-132° C.

EXAMPLE 3 Methyl 4-chloro-4-(2-propenyl)-3,5-cyclohexanedionecarboxylate

38.75 g of methyl 4-(2-propenyl)-3,5-cyclohexanedione carboxylate wasdissolved in 300 ml of tertiary-butanol and 20 g of tertiary-butylhypochlorite in 50 ml of tertiary-butanol was added. The mixture washeated to 50° C. and stirred at that temperature for 3 1/2 hours.Evaporation and drying in vacuo gave methyl4-chloro-4-(2-propenyl)-3,5-cyclohexanedione carboxylate as a viscousoil. (b.p. 95°-100°/0.01 mmHg)

EXAMPLE 4

1-Methoxycarbonyl-3-(2-propenyl)-4-oxo-cyclopent-2-ene

In a three-neck flask equipped with a Dean-Stark separator, vibromixer,and a gas-inlet tube, were placed 600 ml of dry mesitylene and 75 g ofanhydrous sodium carbonate. Argon was bubbled through the reactionmixture in a slow stream during the whole operation. The suspension wasthen heated under reflux for 2 hours before a solution of 45 g of methyl4-chloro-4-(2-propenyl)-3,5-cyclohexanedione carboxylate in 25 ml of drymesitylene was added dropwise during 15 min. to the boiling mixture.Refluxing and vigorous stirring was continued for 16 hours. Filtrationafter cooling, evaporation of the solvent and purification bydistillation gave 20.15 g of1-methoxycarbonyl-3-(2-propenyl)-4-oxo-cyclopent-2-ene; b.p. 106°-111°C/0.75 mmHg.

EXAMPLE 54α-Methoxycarbonyl-3β-nitromethyl-2α-(2-propenyl)cyclopentanone

20.15 g of 1-methoxycarbonyl-3(2-propenyl)-4-oxo-cyclopent-2-ene wasdissolved in 200 ml of nitromethane and 3 ml of a 40 percent by weightmethanolic solution of benzyltrimethylammoniumhydroxide was added. Themixture was then heated on a stream-bath for 3 hours, cooled andacidified with cold 2N aqueous sulfuric acid. The mixture was thenextracted with diethyl ether (300 ml). The ether solution was dried(MgSO₄) and the solvent removed under the reduced pressure. Distillationof the residue afforded4α-methoxycarbonyl-3β-nitromethyl-2α-(2-propenyl)cyclopentanone (b.p.125°-130°/0.15 mmHg)

EXAMPLE 62α-Carboxymethyl-3β-nitromethyl-4α-methoxycarbonylcyclopentanone

To an ice-cold solution of 9.42 g of4α-methoxycarbonyl-3β-nitromethyl-2α-(2-propenyl) cyclopentanone in 75ml of acetone was added an ice-cold solution of 5.8 g of concentratedsulfuric acid in 75 ml of water. With cooling and vigorous stirring asolution of 21.6 g of potassium permanganate in 400 ml of water wasadded dropwise to the reaction mixture during 10 min. The wholeoperation was carried out under an atmosphere of argon. The reactionmixture was stirred for 5 min. Then, sulfur dioxide was bubbled throughthe mixture until a clear solution was obtained. Extraction withmethylene chloride containing 20 percent by weight of acetone andevaporation of the dried (with magnesium sulfate) organic solventafforded4α-methoxycarbonyl-3β-nitromethyl-2α-carboxymethylcyclopentanone. Thecrude product was triturated with diethyl ether and filtered; m.p.148°-150° C.

EXAMPLE 7(-)2-Carboxymethyl-3-nitromethyl-4-methoxycarbonylcyclopentanone

518 mg of 2-carboxymethyl-3-nitromethyl-4-methoxycarbonylcyclopentanonewas dissolved in 25 ml of tetrahydrofuran and 242 mg of(-)α-phenethylamine was added. Addition of a little petroleum ether andcooling gave needles of the salt of (-)α-phenethylamine and(-)2-carboxymethyl-3-nitromethyl-4-methoxycarbonylcyclopentanone whichupon two recrystallizations had a constant m.p. 124°-125° C. [α]_(D)-52.46 (C.1.04, H₂ O). Acidification with Dowex 50W-X8 (H⁺) gave thesolid, levo-rotating (-)2-carboxymethyl-3-nitromethyl-4-methoxycarbonylcyclopentanone; m.p.111°-112° C.; [α]_(D) -79.9 (C,1.0 MeOH).

EXAMPLE 8(+)2-Carboxymethyl-3-nitromethyl-4-methoxycarbonylcyclopentanone

Utilizing the procedure of Example 7, (+)α-phenethylamine gave the saltof (+)α-phenethylamine and(+)2-carboxymelthyl-3-nitromethyl-4-methoxycarbonylcyclopentanone; m.p.122°-123° C., [α]_(D) +58.02 (C,1.0, H₂ O). Acidification gave thedextro-rotating(+)2-carboxymethyl-3-nitromethyl-4-methoxycarbonylcyclopentanone;m.p. 112°-113° C. [α]_(D) +84.28 (C, 1.0, MeOH).

EXAMPLE 9 3,3abeta-4,5,6,6a-beta-hexahydro-4β-nitromethyl-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methylester

To an ice-cooled solution of 4.66 g of2α-carboxymethyl-3β-nitromethyl-4β-methoxycarbonylcyclopentanone in 250ml of methanol was added 0.94 g of sodium methoxide followed by theaddition of 0.5 g of sodium borohydride. The mixture was stirred at 0°C. for 1 hour and then acidified with 1N-aqueous sulfuric acid.Evaporation of the methanol left2α-carboxymethyl-3β-nitromethyl-4α-methoxycarbonylcyclopentanol as aliquid residue which was extracted with a 20% by volume acetone in 80%ethyl acetate solution. The solution was dried and the solvent removedunder reduced pressure. The residue was then dissolved intetrahydrofuran and refluxed for 2 hours. The solvent was then removedand the residue treated with 15 ml. of water containing 2 g. ofpotassium bicarbonate. The solid was filtered to give 3,3a beta-4,5,6,6abeta-hexahydro-4β-nitromethyl-2-oxo-2H-cyclopenta[b]furan-5α-carboxylicacid methylester; m.p. 100°-101.5° C. Recrystallization from ethylacetate petroleum ether raised the m.p. to 102°-103° C.

The bicarbonate solution was acidified and extracted with a 2:1 parts byvolume solution of methylene chloride-acetone. The organic solution wasdried (MgSO₄). The solvent was removed under reduced pressure. Theresidue was then crystallized from ethylacetate-petroleum ether to give2α-carboxymethyl-3β-nitromethyl-4α-methoxycarbonyl-cyclopentane-1β-ol,m.p. 98°-100° C.

EXAMPLE 10 3,3a beta-4,5,6,6abeta-hexahydro-4β-aminomethyl-2-oxo-2-2H-cyclopenta [b]furan-5α-carboxylic acid methylester hydrochloride

635 l mg. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-nitromethyl-2-oxo-2H-cyclopenta[b] furan-5α-carboxylicacid methylester was dissolved in 100 ml. of ethanol and hydrogenated inthe presence of 190 mg. of platinum oxide at room temperature in a Parrhydrogenator (53 p.s.i.) for 3 1/2 hours. The catalyst was filtered off,the filtrate evaporated, and the free amine residue treated withethanolic hydrogen chloride. The ethanol was removed under reducedpressure and the remaining solid suspended in an ethanol-ethyl acetatemixture and filtered giving 605 mg. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-aminomethyl-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester hydrochloride; m.p. 260° C. dec.Recrystallization from aqueous methanol raised the melting point to 261°C. dec.

EXAMPLE 11 3,3a beta-4,5,6,6abeta-hexahydro-4β-carboxyaldehyde-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester

243 mg. of 3,3a beta-4,5,6,6abeta-hexahydro-4-nitromethyl-2-oxo-2H-cyclopenta [b] furan-5α-carboxylicacid methylester was dissolved in 20 ml. of methanol to which 1equivalent of lithium methoxide had been added. The clear solution,containing the acinitro salt was evaporated, the residue taken up in 5ml. of cold water, and 2 drops of 20% by weight aqueous potassiumhydroxide were added. With ice-cooling and stirring, a solution of 130mg. of sodium permanganate trihydrate in 5 ml. of water was addeddropwise over a period of 3 minutes. The reaction mixture was thenquickly filtered, and the residue washed with methylene chloride. Thefiltrate was extracted with more methylene chloride. Evaporation of thedried (MgSO₄) organic solvent afforded the aldehyde 3,3abeta-4,5,6,6a-beta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester m.p. 94-96. A2,4-d-nitrophenylhydrazone of the aldehyde had a melting point of187°-189° C.

EXAMPLE 12 3,3a beta-4,5,6,6abeta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester

To a suspension of 305 mg of 3,3a beta-4,5,6,6abeta-hexahydro-4β-aminomethyl-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester hydrochloride in 25 ml. of methanolwas added 5 ml. of ion exchange resin A-540 (OH--), and the mixturestirred for 15 minutes. Filtration and evaporation gave 260 mg. of thefree amine, i.e., 3,3a beta-4,5,6,6abeta-hexahydro-4β-aminomethyl-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester. The free amine was dissolved in 30ml. of t-butanol and treated at 50° C. with 135 mg. of tertiary butylhypochlorite dissolved in 5 ml. of tertiary butanol. The mixture waskept at 50° C. for 30 minutes. Evaporation of the organic solventafforded the N-chloroaminomelthyl derivative, i.e., 3,3a beta-4,5,6,6abeta-hexahydro-4β-chloroaminomethyl-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester. This derivative was suspended in 8ml. of methanol and treated with a solution of 66 mg. of sodiummethoxide in 5 ml. of methanol. The clear solution was then heated underreflux until neutral (2 hours). Cooling and evaporation gave the 3,3abeta-4,5,6,6a beta-hexahydro-4β-iminomethyl-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methyl ester. This compound was then hydrolyzedwith 0.1 N aqueous hydrochloric acid to form 3,3a beta-4,5,6,6abeta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methylester.

EXAMPLE 13 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3-oxo-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester

To a solution of 433 mg. of dimethyl (2-oxoheptyl)-phosphonate in 20 ml.of dimethoxy ethylene glycol was added under an argon atmosphere 1.2 ml.of a 1.6 M solution of n-butyl lithium in hexane. After 10 minutes, 400mg. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester was added and the mixture stirredfor 2 hours. Water was then added (25 ml.) and the mixture extractedwith methylene chloride. The methylene chloride solution was dried(MgSO₄), treated with activated charcoal and the solvent removed underreduced pressure to give 600 mg. of a brown oil. The product was takenup in a little ethyl acetate, filtered through a small column of silicagel, and the eluate treated with petroleum ether. After 2 days at 0° C.the 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3-oxo-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methylester, crystallized as large flat prisms;m.p. 48°-49° C.

EXAMPLE 14 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester

5 g. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3oxo-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester was treated with excess zincborohydride in 50 ml. of dimethoxy ethylene glycol at room temperature(25° C.) for half an hour. After cautious addition of 30 ml. of dilutesulfuric acid, with ice-cooling, the mixture was extracted four timeswith diethyl ether. Evaporation of the ether gave a mixture from whichthe pure 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester m.p. 58°-61° C. was obtained uponchromatography on silica gel (diethyl ether as eluant). Also obtained bychromatography was the 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3β-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester which was a colorless oil.

EXAMPLE 15

A mixture of 6.1 g. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methylester in 40 ml. of tetrahydrofuran and 9ml. of 6% by weight aqueous sodium hydroxide was refluxed 3.5 hours. Themixture was cooled with an ice bath and slowly acidified with 2N-aqueoussulfuric acid. After evaporation of most of the tetrahydrofuran, theresidue was saturated with sodium chloride and extracted with ethylacetate. Evaporation of the ethyl acetate gave 6.0 g. of2β-(3α-hydroxy-1-trans-octenyl)3β-carboxymethyl-4α-hydroxy-cyclopentane-1α-carboxylicacid.

A benzene solution of the acid was refluxed in a Deank-Stark apparatusuntil thin layer analysis showed the lactonization was complete.Evaporation of the benzene yielded 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid.

EXAMPLE 16

0.1 ml. of acetic anhydride was added at 0° C. to a solution of 0.96 g.of 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-hydroxy-1-trans-ocetnyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid in 15 ml. of pyridine. After standing at 25° C.for 15 hours, the reaction mixture was cooled to 0° C. and 3 ml. ofwater added. After 2 hours, the pyridine was evaporated and the residuedissolved in ethyl acetate. The ethyl acetate solution was washed with4N-hydrochloric acid then evaporated to yield 1.12 g. of3,3αbeta-4,5,6,6abeta-hexahydro-4β-(3α-acetoxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid, m.p. 34°-36° C. from ethyl ether.

EXAMPLE 17

0.94 g. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-acetoxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid was reacted with 2 ml. of oxalyl chloride in 10ml. of benzene at 40° C. for 30 minutes. The excess oxalyl chloride andbenzene were evaporated to yield 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-acetoxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid chloride. This chloride and 0.48 g. of 97%M-chloroperbenzoic acid were dissolved in 5 ml. of benzene and 0.4 ml.of pyridine was slowly added at 0° C. After 2 hours, 70 ml. of benzenewas added and the resulting solution washed successively with2N-hydrochloric acid, 10% by weight aqueous sodium bicarbonate, andsaturated sodium chloride. Evaporation of the benzene at 10°-20° C.yielded 3,3a beta-4,5,6,6a beta-hexahydro-4β-(3α-acetoxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b] furan-5α-oyl m-chlorobenzoylperoxide, m.p. 79°-80° C.

EXAMPLE 18

A solution of 0.9 g. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-acetoxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-oyl m-chlorobenzoyl peroxide in 45 ml. of benzene was refluxedfor 24 hours. The benzene was evaporated to produce a mixture containing3,3a beta-4,5,6,6a beta-hexahydro-4 beta-(3alpha-acetoxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-(3-chlorobenzoyloxy) and 3,3a beta-4,5,6,6a beta-hexahydro-4beta-(3α-acetoxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-(3-chlorobenzoylcarbonyldioxy) as residue. This residue wasdissolved in 10 ml. of 2.3 M lithium methoxide in methanol. After onehour, the reaction was acidified with 4N-hydrochloric acid, saturatedwith sodium chloride, and extracted with methylene chloride. Thecombined methylene chloride extracts were washed with 10% by weightaqueous sodium bicarbonate, then evaporated to yield 0.65 g. ofmaterial. Chromatography on silica gel afforded 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-hydroxy-1-trans-octenyl)-5α-hydroxy-2-oxo-2H-cyclopenta [b] furan.

EXAMPLE 19

A solution of 2.6 g. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-(3α-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acid methyl ester, 6.9 g. of dihydropyran and 14 mg.of p-toluene-sulfonic acid in 150 ml. of methylene chloride was stirredat 25° C. for 3 hours. The solution was washed with saturated sodiumbicarbonate and the volatile components evaporated to give 4 g. of anoil. The oil was dissolved in 1.1 parts by volume ethyl ether-hexane andstored at -17° C. After one day 3,3a beta-4,5,6,6abeta-hexahydro-4β-[3α(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b] furan-5α-carboxylic acid methyl ester crystallized as needles; m.p.64°-65° C.

EXAMPLE 20

A mixture of 1.88 g. of 3,3a beta-4,5,6,6abeta-hexahydro-4β[3α(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan-5α-carboxylicacid methylester, 8.3 ml. of 6% by weight aqueous solution of sodiumhydroxide and 33 ml. of tetrahydrofuran was refluxed for 4 hours. Themixture was cooled to 0° C. and neutralized with 2N-aqueous sulfuricacid, saturated with sodium chloride, and extracted with ethyl acetate.Evaporation of the ethyl acetate yielded 2.5 g. of 2β[3α(2-tetrahydropyranyloxy)-1-trans-octenyl]-3α-carboxymethyl-4α-hydroxy-cyclopentane-1α-carboxylicacid; m.p. 114-115° C.

The acid was mixed with 50 ml. of benzene and the mixture refluxed for 4hours. Evaporation of the benzene yielded 3,3a beta-4,5,6,6abeta-hexahydro-4β[3α(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan-5α-carboxylicacid; m.p. 73°-74° C. from ethyl ether/hexane.

EXAMPLE 21

A solution of 198 mg. of 3,3a beta-4,5,6,6a beta-hexahydro-4β[3α(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid and 88 mg. of 97% m-chloroperbenzoic acid in7 ml. of ethyl ether/methylene chloride (1:1 parts by volume) was addedto an ice cold solution of 110 mg. of dicyclohexylcarbodiimide in 2.5ml. of ethyl ether. The mixture was kept at -3° C. for 15 hours, thenfiltered and the filtrate washed successively with saturated ammoniumsulfate, 10% sodium bicarbonate; and saturated sodium chloride.Evaporation of the solvent below 25° C. yielded 248 mg. of 3,3abeta-4,5,6,6a beta-hexahydro-4β[3α(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan-5α-oyl m-chloro-benzoylperoxide.

EXAMPLE 22

The compound of 3,3a beta-4,5,6,6abeta-hexahydro-4β[3α(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan-5α-oyl-m-chlorobenzoylperoxide was treated in the manner of Example 18 to form 3,3abeta-4,5,6,6abeta-hexahydro-4β[3α(2-tetrahydropyranyl)-1-trans-octenyl]-5.alpha.-hydroxy-2-oxo-2H-cyclopenta[b]furan.

This product was then hydrolyzed with 10% aqueous acetic acid intetrahydrofuran to produce 3,3a beta-4,5,6,6a beta-hexahydro-4β(3α-hydroxy-1-trans-octenyl)-5α-hydroxy-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 23

3,3a beta-4,5,6,6abeta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta[b]furan-5α-carboxylicacid methylester oxime

To a solution of 1.8 g. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-aminomethyl-2-oxo-2H-cyclopenta[b]furan-5α-carboxylicacid methyl ester in 15 ml. of methanol was added 0.5 g. of sodiumtungstate followed by the dropwise addition of 3 ml. of 30-35% aqueoushydrogen peroxide. The temperature was maintained at 15°-20° C.throughout the addition and for 0.5 hours thereafter. The methanol wasthen removed under reduced pressure and the residue extracted thoroughlywith ethyl acetate. The organic layer was dried (MgSO₄) and the solventremoved under reduced pressure to give the 3,3a beta-4,5,6,6abeta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methylester oxime.

EXAMPLE 24

3,3a beta-4,5,6,6abeta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta[b]furan-5α-carboxylicacid methyl ester

To a solution of 1 g. of 3,3a beta-4,5,6,6a beta-hexahydro-4β-carboxaldehyde-2-oxo-2H-cyclopenta[b]furan-5αcarboxylic acid methylester oxime dissolved in 15 ml. of a 50% by volume aqueous ethanolicsolution was added 1.5 g. of sodium bisulfite. The resulting mixture wasthen refluxed for two hours and the ethanol removed under reducedpressure. The residue was then treated with dilute hydrochloric acid andthe mixture extracted with chloroform. The organic layer was dried(MgSO₄) and the solvent removed under reduced pressure to give 3,3abeta-4,5,6,6a beta-hexahydro-4β-carbox-aldehyde-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methyl ester.

EXAMPLE 25 4α-Methoxycarbonyl-3β-cyano-2α-(2-propenyl)cyclopentanone

To a solution of diethylaluminumcyanide (0.2 mole) in 150 ml. of tolueneat 0° C. was added a solution of 16 g. of 1-methoxy-carbonyl-3-(2-propenyl)-4-oxo-cyclopent-2-ene dissolved in 100 ml. oftoluene. After 30 minutes the mixture was poured slowly onto ice-cold2N-hydrochloric acid and extracted with methylene chloride. The organicextract was dried (MgSO₄) and the solvent removed under reduced pressureto give a residue which after distillation afforded the4α-methoxycarbonyl-3β-cyano-2α-(2-propenyl)cyclopentanone.

EXAMPLE 26

By the procedure of Example 6, 2α-methoxycarbonyl-3β-cyano-2α-(2-propenyl)-cyclopentanone was converted to 2α-carboxymethyl-3β-cyano-4α-methoxycarbonyl-cyclopentanone.

EXAMPLE 27 3,3a beta-4,5,6,6abeta-hexahydro-4β-cyano-2-oxo-2H-cyclopenta [b]furan-5α-carboxylic acidmethylester

To an ice-cold solution of 4.66 g. of 2α-carboxymethyl-3β-cyano-4α-methoxycarbonylcyclopentanone in 250 ml. of methanol was added0.94 g. of sodium methoxide followed by the addition of 0.5 g. of sodiumborohydride. The mixture was stirred at 0° C. for 1 hour and thenacidified with 1N-aqueous sulfuric acid. Evaporation of the methanolleft 2α-carboxymethyl-3β-cyano-4α- methoxycarbonylcyclopentanol as aliquid residue which was extracted with a 20% by volume acetone in 80%ethyl acetate solution. The solution was dried and the solvent removedunder reduced pressure. The residue was then dissolved intetrahydrofuran and refluxed for 2 hours. The solvent was then removedand the residue treated with 15 ml. of water containing 2 g. ofpotassium bicarbonate. The solid was filtered to give 3,3a beta-4,5,6,6abeta- hexahydro-4β-cyano-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acidmethylester.

EXAMPLE 28 3,3a beta-4,5,6,6a beta-hexahydro-4β-aminomethyl-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methylester hydrochloride

635 mg. of 3,3a beta-4,5,6,6a beta-hexahydro-4β-cyano-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methylester was dissolvedin 100 ml. of ethanol and hydrogenated in the presence of 190 mg. ofplatinum oxide at room temperature in a Parrhydrogenator (53 p.s.i.) for31/2 hours. The catalyst was filtered off, the filtrate evaporated, andthe free amine residue treated with ethanolic hydrogen chloride. Theethanol was removed under reduced pressure and the remaining solidsuspended in an ethanol ethyl-acetate mixture and filtered giving 605mg. of 3,3a beta-4,5,6,6abeta-hexahydro-4β-aminomethyl-2-oxo-2H-cyclopenta [b]furan-5α-carboxylicacid methylester hydrochloride.

EXAMPLE 29 2-Allyl-1,3-cyclohexanedione

Allyl bromide (195 g., 1.62 mol.) was added over a 15 minute period to astirred ice-cold mixture of cyclohexanedione (165 g., 1.47 mol.),copperbronze (4.5 g.), and 330 ml. of 20% by weight aqueous potassiumhydroxide. After 6 hours, the reaction was mixed with 1500 ml. of a 5%by weight aqueous sodium hydroxide solution and 1000 ml. of ethyl ether,filtered and the separated water layer acidified with 4N aqueoushydrochloric acid to pH 1. A brown solid (188 g.) formed uponrefrigeration at 0° C. The solid was taken up in ethyl acetate and thesolution was washed with water (3 × 150 ml.), dried (MgSO₄), treatedwith charcoal, and condensed until turbid. Upon cooling, 126 g. (57%) of2-allyl-1,3-cyclohexanedione was collected, m.p. 125°-127° C.

EXAMPLE 30

By the procedure of Example 29, allyl bromide is reacted with 5-methyl-1,3-cyclohexanedione to produce2-allyl-5-methyl-1,3-cyclohexanedione.

EXAMPLE 31 2-Chloro-2-allyl-1,3-cyclohexanedione

t-Butylhypochlorite (104.6 g, 0196 mol) was added dropwise to a solutionof 2-allyl-1,3-cyclohexanedione (132 g, 0.87 mol) in 650 ml of methanolat 0° C. The temperature was not allowed to rise above 20° C. Themethanol was removed at reduced pressure in a 40° water bath and theresidual oil was taken up in benzene. The benzene solution was washedwith 5 percent sodium thiosulfate (3 × 250 ml), 5 percent sodiumbicarbonate (3 × 250 ml) and water (1 × 250 ml). Evaporation of thebenzene gave 148 g (91 percent) of 2-chloro-2-allyl-1,3-cyclohexanedioneas a light yellow oil.

EXAMPLE 32

By the procedure of Example 31 2-allyl-5-methyl-1,3-cyclo- hexanedionewas converted to 2-chloro-2-allyl-5-methyl-1,3-cyclohexanedione.

EXAMPLE 33 2-Allyl-2-cyclopenten-1-one

Anhydrous powdered sodium carbonate (670 g) and 1300 ml of dry (alumina)xylene were placed in a 3-1., three-necked flask equipped with aDean-Stark trap, condenser, vibra-mixer, dropping funnel and argoninlet. The flask was flushed with argon and the contents brought toreflux. A solution of 2-chloro-2-allyl-1, 3-cyclohexanedione (147 g,0.79 mol) in 200 ml of xylene was added dropwise at such a rate thatstrong refluxing was maintained. After 4.5 hr, the reaction was cooled,filtered, and the sodium carbonate cake washed thoroughly with ethylacetate. Evaporation of the solvent and careful fractionization of theresidual oil gave 47.8 g (50 percent) of 2-allyl-2-cyclopenten-1-one, bp73°-84° /4.2 mm.

EXAMPLE 34

By the procedure of Example 332-chloro-2-allyl-5-methyl-1,3-cyclohexanedione was converted to2-allyl-4-methyl-2-cyclo- penten-1-one.

EXAMPLE 35 2-alpha-Allyl-3-beta-nitromethylcyclopentaneone

A solution of 2-allyl-2-cyclopenten-1-one (46.8 g, 0.38 mol), 180 ml ofnitromethane and 12 ml of Triton B¹ (35 percent by weight in methanol)was heated for 4 hr in an oil bath at 60°-65° C. The reaction mixturewas cooled, acidified to pH 1 with 1N aqueous sulfuric acid, dilutedwith 500 ml of ethyl ether, washed with saturated aqueous sodiumchloride solution (2 × 250 ml), and dried (MgSO₄). Evaporation of thesolvent gave 69 g (100 percent) of 2-alpha-allyl-3beta-nitromethylcyclopentaneone as a yellow oil. The compound can befurther purified by distillation, bp 110°-112° /0.025 mmHg.

EXAMPLE 36

By the procedure of Example 35 2-allyl-4-methyl-2-cyclo- penten-1-onewas converted to 2-alpha-allyl-3 beta-nitromethyl-4alpha-methylcyclopentan-1-one.

EXAMPLE 37 2-alpha-Carboxymethyl-3 beta-nitromethylcyclopentan-1-one

A solution of sodium permanganate (52.2 g, 0.26 mol) in 140 ml of waterwas added dropwise over a 1 hr period to a rapidly stirred mixture of2-alpha-allyl-3 beta-nitromethylcyclopentaneone (18.3 g, 0.1 mol), 300ml of acetone, and 83 ml of 10 percent (v/v) sulfuric acid under argonat -10°-0° . The reaction was stirred an additional 45 min at 0° C.,then saturated with sodium chloride and extracted with 3:7tetrahydrofuran-methylene chloride. The combined organic extracts weredried (MgSO₄) and evaporated to give 23.2 g of crude 2alpha-carboxymethyl-3 beta-nitromethylcyclopentan-1-one as an oil whichcrystallized from ethyl acetate-ethyl ether (1:4); mp 88°-90° C.

EXAMPLE 38

By the procedure of Example 37, 2 alpha-allyl-3 beta- nitromethyl-4alpha-methylcyclopentan-1-one was converted to 2 alpha-carboxymethyl-3beta-nitromethyl-4 alpha-methyl cyclo- pentan-1-one.

EXAMPLE 39 3,3a beta-4,5,6,6a beta-Hexahydro-4beta-nitromethyl-2-oxo-2H-cyclopenta[b]furan

A solution of compound 2 alpha-carboxymethyl-3 beta-nitro-methylcyclopentan-1-one (2.01 g, 10 mmol) in 20 ml of tetrahydrofuranwas treated dropwise under argon at -78° C. with 20 ml (21.6 mmol) of a1.06 M tetrahydrofuran solution of lithiumperhydro-9b-boraphenalylhydride. The reaction was stirred for 30 minthen allowed to warm to 0° C. At this point it was poured into aseparatory funnel containing 200 ml of cyclohexane, 150 ml of ethylacetate, and 50 ml of water. The water layer was separated and theorganic phase washed with water (2 × 20 ml). The combined water extractswere immediately acidified to pH 1 with 4N aqueous hydrochloric acid,saturated with sodium chloride and extracted with 3:7 parts by volumetetrahydrofuran-methylene chloride (3 × 50 ml) solution. The combinedorganic extracts were dried (MgSO₄) and condensed to give 2.1 g of acolorless oil which was taken up in 200 ml of benzene and refluxed for 2hr in a Dean-Stark apparatus. The resulting benzene solution was washedwith 5 percent by weight aqueous sodium bicarbonate (2 × 10 ml), dried(MgSO₄), and condensed to give 1.15 g (62 percent) of 3,3a beta-4,5,6,6abeta-hexahydro-4 beta-nitromethyl-2-oxo-2H-cyclopenta[b]furan as acolorless oil.

EXAMPLE 40

By the procedure of Example 39, 2 alpha-carboxymethyl-3 beta-nitromethyl-4 alpha-methyl cyclopentan-1-one is converted to 3,3abeta-4,5,6,6a beta-hexahydro-4-beta nitromethyl-5 alpha-methyl-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 41 3,3a beta-4,5,6,6abeta-Hexahydro-4-beta-nitromethyl-2-oxo-2H- cyclopenta[b]furan and 2alpha-Carboxymethyl-3 beta-nitromethyl-1-cyclopentane-1 beta-ol

To an ice cold solution of 3.8 g of 2 alpha-carboxymethyl-3beta-nitromethylcyclopentan-1-one in 200 ml of methanol was added 1.08 gof sodium methoxide followed by 0.6 g of sodium borohydride. The mixturewas stirred at 0° C. for 1 hr and then acidified with 1N aqueoussulfuric acid. Evaporation of the methanol left 2 alpha-carboxymethyl-3beta-nitromethyl-4 alpha- methylcyclopentanol as a liquid residue whichwas extracted with a 20 percent by volume acetone in ethylacetatesolution. The solution was dried and the solvent removed under reducedpressure. The residue was then dissolved in tetrahydrofuran and refluxed2 hr. The solvent was then removed and the residue treated with 15 ml ofwater containing 2 g of potassium bicarbonate. The mixture was extractedwith methylene chloride and the organic layer dried (MgSO₄). The solventwas then removed under reduced pressure to give the 3,3a beta-4,5,6,6abeta- hexahydro-4 beta-nitromethyl-2-oxo-2H-cyclopenta[b]furan.

The bicarbonate solution was acidified and extracted with 2:1 parts byvolume of a solution of methylenechloride-acetone. The organic solutionwas dried (MgSO₄) and the solvent removed under reduced pressure to give2 alpha-carboxymethyl-3 beta- nitromethyl-1-cyclopentane-1 beta-ol, mp84°-85° C.

EXAMPLE 42

By the procedure of Example 41 2 alpha-carboxymethyl-3beta-nitromethyl-4 alpha-methyl cyclopentan-1-one is converted into theisomers 3,3a beta-4,5,6,6a beta-hexahydro-4 beta nitro- methyl-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan and 2 alpha- carboxymethyl-3beta-nitromethyl-5 alpha-methyl-1-cyclopentan-1 beta-ol.

EXAMPLE 43 3,3a beta-4,5,6,6a beta-Hexahydro-4beta-formyl-2-oxo-2H-cyclopenta[b]furan

A solution of 3,3a beta-4,5,6,6a beta-hexahydro-4 beta-nitromethyl-2-oxo-2H-cyclopenta[b]furan (1.08 g, 4.85 mmol) in 35 ml ofabsolute methanol was treated at 0° C. under argon with 2.6 ml (6.0mmol) of a 2.3 M lithium methoxide in methanol solution. The solvent wasevaporated and the residual solid dried at 25° C. in vacuo. To the drysalt under argon at -10°-0° C. was added 15 ml of saturated boraxsolution followed by the dropwise addition of sodium permanganatetrihydrate (0.69 g, 3.5 mmol) in 6 ml of water. The reaction mixture wasimmediately filtered through celite and extracted with 8:2 methylenechlorideacetone (4 × 60 ml). Evaporation of the dried (MgSO₄) organicextracts gave 0.50 g (55 percent of 3,3a beta-4,5,6,6a b etahexahydro-4beta-formyl-2-oxo-2H-cyclopenta[b]furan as an oil.

EXAMPLE 44

By the procedure of Example 43, 3,3abeta-4,5,6,6abeta-hexahydro-4betanitromethyl-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan was converted to3,3abeta-4,5,6,6abeta-hexahydro-4beta-formyl-5alphamethyl-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 453,3abeta-4,5,6,6abeta-hexahydro-4beta-(3-oxo-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan

To a suspension of 0.72 g. of sodium hydride in 150 ml. of dry glyme wasadded 6 g. of dimethyl(2-oxoheptyl) phosphonate. After stirring for 1.5hour, 5 g. of3,3abeta-4,5,6,6abeta-hexahydro-4beta-formyl-5alpha-methyl-2-oxo-2H-cyclopenta[b]furandissolved in 30 ml. of glyme was added dropwise at 0° C. After stirringfor 3 hours at room temperature, 500 ml. of diethyl ether was added andthe mixture washed with water. The organic layer was then dried (MgSO₄)and the solvent removed under reduced pressure. The residue was thenwashed through 75 g. of silica gel to give 7.1 g. of 3,3abeta-4,5,6,6abeta-hexahydro-4beta-(5-oxo-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 46

By the procedure of Example 45, 3,3abeta-4,5,6,6abeta-hexahydro-4beta-formyl-2-oxo-2H-cyclopenta[b]furan was converted to3,3abeta-4,5,6,6a beta-hexahydro-4beta-(5-oxo-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 47 3,3a beta-4,5,6,6a beta-Hexahydro-4beta(3alpha-hydroxy-1-transoctenyl) -5alpha-methyl-2-oxo-2H-cyclopenta[b]furan

To solution of 4.5 g of 3,3a beta-4,5,6,6a beta-hexahydro-4beta-(3-oxo-1-trans-octenyl)-5 alpha-methyl-2-oxo-2H-cyclopenta[b] furanin 100 ml of dry glyme was added an excess of zinc borohydride in 50 mlof glyme and the resulting solution stirred for 3 hr. The solution wascooled to 0° centigrade and treated with 200 ml of water, 400 ml ofether and 10 ml of 0.5N aqueous sulfuric acid. The ether was separatedand dried (MgSO₄) and the solvent removed under reduced pressure to give3,3a beta-4,5,6,6a beta-hexahydro-4 beta-(3-hydroxy-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan. Chromatography on silice gelthen afforded the 3,3a beta-4,5,6,6a beta-hexahydro-4 beta-(3alphahydroxy-1-trans-octenyl)5 beta-methyl-2-oxo-2H-cyclopenta[b]furan.Also obtained by chromatography was the 3,3a beta -4,5,6,6abeta-hexahydro-4 beta(3 beta-hydroxy-1-trans-octenyl)-5 beta-methyl-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 48

By the procedure of Example 47, 3,3a beta-4,5,6,6a betahexahydro-4beta-(3-oxo-1-trans-octenyl)-2-oxo-2H-cyclopenta[b] furan was convertedto 3,3a beta-4,5,6,6a beta-hexahydro-4 beta (3beta-hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 49 3,3a beta-4,5,6,6a beta-Hexahydro-4-beta-[3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-5alpha-methyl-2-oxo-2H-cyclopenta-[b]furan

A solution of 5 g of 3,3a beta-4,5,6,6a beta-hexahydro-4 beta-(3alpha-hydroxy-1-trans-octenyl)-5alpha-methyl-2-oxo-2H-cyclopenta[b]furan, 12 g of dihydropyran and 25 mgof p-toluene sulfonic acid in 200 ml of methylene chloride was stirredat 25° C. for 3 hr. The solution was washed with saturated sodiumbicarbonate solution, the methylene chloride solution dried (MgSO₄) andthe volatile components evaporated under reduced pressure to give 6.4 gof 3,3a beta-4,5,6,6a beta-hexahydro-4 beta[3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alphamethyl-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 50

By the procedure of Example 49, 3,3a beta-4,5,6,6a beta-hexahydro 4 beta-(3 beta-hydroxy-1-trans-octenyl)-2-oxo-2H cyclopenta [b]furan wasconverted to 3,3a beta-4,5,6,6a beta-hexahydro-4 beta[3-alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan.

EXAMPLE 51 3,3a beta-4,5,6,6a beta-Hexahydro-4 beta[3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha-methyl-2-hydroxy-2H-cyclopenta[b]furan

To a solution of 5.3 g of 3,3a beta-4,5,6,6a beta-hexahydro-4beta-[3alpha(2 tetrahydropyyranyloxy)-1-trans-octenyl]5alphamethyl-2-oxo-2H-cyclopenta[b]furan in 150 ml of toluene, was addeddropwise at -73° C., 2 equivalents of diisobutylaluminum hydride in thesame solvent. The reaction mixture was stirred at this temperature for 2hr after which time 20 ml of methanol was slowly added and the mixturestirred for 2 hr at room temperature. The mixture was then filtered thrua bed of charcoal, the charcoal was washed with ethyl acetate and thesolvents were then removed under reduced pressure. The residue was thenwashed thru a column of silica gel to give 3,3a beta-4,5,6,6abeta-hexahydro-4 beta [3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha-methyl-2-hydroxy-2H- cyclopenta[b]furan.

EXAMPLE 52

By the procedure of Example 51, 3,3a beta-4,5,6,6a beta hexahydro-4beta-[3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]-2-oxo-2H-cyclopenta[b]furan was converted to 3,3a beta-4,5,6,6a beta-hexahydro-4 beta[3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl)-2-hydroxy-2H-cyclopenta[b]furan.

EXAMPLE 53 7-[[3 alpha-methyl-5 alpha-hydroxy-2 beta[3alpha(2-tetrahydro-pyranyloxy)-1-trans-octenyl]cyclopentyl]]-cis-5-heptenoicacid

A solution of 200 mg of 3,3a beta-4,5,6,6a beta-hexahydro-4 beta[3alpha(2-tetrahydropyranyloxy)-1-trans-octenyl]5alpha-methyl-2-hydroxy-2H-cyclopenta[b]furan in 3 ml ofdimethylsulfoxide was added to 10 ml of a solution of 2.8 equivalents ofthe Wittig reagent prepared from 4-carboxybutyltriphenylphosphoniumbromide and dimsylsodium. After 3 hr at 25° C. the mixture was pouredinto 30 ml of dilute brine and acidified to pH 3 with phosphoric acid.The mixture was extracted with pentane and the product separated bycolumn chromatography to give 7 [[3 alpha-methyl-5 alpha-hydroxy-2beta[3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]cyclopentyl]]-cis-5-heptenoicacid.

EXAMPLE 54

By the procedure of Example 53, 3,3a beta-4,5,6,6a betahexahydro-4beta[3 alpha(2-tetrahydropyranyloxy)-1-trans-octenyl)-2hydroxy-2H-cyclopenta[b]furan is converted to 7 [[5-alpha-hydroxy-2 beta[3 alpha-(2-tetrahydropyranyloxy)-1-trans octenyl]cyclopentyl]]-cis-5-heptenoic acid.

EXAMPLE 55 7[3 alpha-Methyl-5-oxo-2 beta (3alpha-hydroxy-1-trans-octenyl) cyclopentyl]cis-5-heptenoic acid

To a mixture of 6 g of chromium trioxide and 9.5 g of pyridine in 150 mlof methylene chloride was added at 0° C 4.5 g of 7[[3 alpha-methyl-5alpha-hydroxy-2 beta[3 alpha-(2-tetrahydropyranyloxy)-1-trans-octenylcyclopentyl]] cis-5-heptenoic acid dissolved in 50 ml of methylenechloride. The mixture was stirred for 1 hr at room temperature and themixture filtered thru a bed of celite. The celite was washed withmethylene chloride and the combined methylene chloride solution washedwith dilute hydrochloric acid to remove any remaining pyridine. Themethylene chloride was then removed under reduced pressure and theresidue treated with 50 ml of 3:1 parts by volume acetic acid/watersolution at 35° C. for 15 hr. The solvents were then removed under highvacuum and the residue purified by column chromatography to give 7-[3alpha-methyl-5-oxo-2 beta(3 alpha-hydroxy-1-trans-octenyl)cyclopentyl]cis-5-heptenoic acid.

EXAMPLE 56

By the procedure of Example 55, 7[[5-alpha-hydroxy-2 beta [3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]cyclopentyl]]-cis-5-heptenoicacid was converted to 7[5-oxo-2 beta(3alpha-hydroxy-1-trans-octenyl)cyclopenyl]cis-5-heptenoic acid.

EXAMPLE 57 7[3 alpha-Methyl-5 alpha-hydroxy-2 beta(3alpha-hydroxy-1-trans-octenyl)cyclopentyl]cis-5-heptenoic acid

A solution of 200 mg of 7-[[3 alpha-methyl-5 alpha-hydroxy-2 beta[3alpha-(2-tetrapyranyloxy)-1-trans-octenyl]cyclopentyl]]-cis-5-heptenoicacid in 5 ml of a 3:1 parts by volume acetic acid/water solution waskept at 35° C. for 15 hr. The solvent was then removed under high vacuumand the residue purified via column chromatography to give 7[3alpha-methyl-5 alpha-hydroxy-2 beta(3alpha-hydroxy-1-trans-octenyl)cyclopentyl]cis-5-heptenoic acid.

EXAMPLE 58

By the procedure of Example 57, 7[[ 5 alpha-hydroxy-2 beta [3alpha-(2-tetrahydropyranyloxy)-1-trans-octenyl]cyclopentyl]]-cis-5-heptenoicacid was converted to 7[3 alpha-hydroxy-2 beta (3alpha-hydroxy-1-trans-octenyl)cyclopentyl]cis-5-heptenoic acid.

We claim:
 1. A compound of the formula: ##STR30## wherein R₉ is loweralkanozloxy, benzoyloxy, benloxy or tetrahydropyranyloxyand enantiomersand racemates thereof.